OASIS-7

CURRENT OASIS 7: A 2X2 Factorial

Randomized Trial of Optimal
Clopidogrel and Aspirin Dosing in
Patients with ACS Undergoing an Early
Invasive Strategy with Intent For PCI
Shamir R. Mehta on behalf of the CURRENT Investigators

Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers
Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and
the trial was overseen by an international steering committee of experts.
 Background

Clopidogrel
• Clopidogrel 300 mg followed by 75 mg daily reduces major
CV events across the spectrum of ACS and PCI
• Recent data suggest that doubling the loading and
maintenance doses of clopidogrel results in a higher and
more rapid antiplatelet effect

Aspirin
• Dose of ASA varies between Europe and North America
• No large-scale RCT’s have compared high (300-325 mg)
versus low (75-100) dose aspirin in patients with ACS
undergoing PCI
 Benefits of Antiplatelet Therapy in ACS are
Greater in Patients Undergoing PCI

Relative Risk Reduction

PCI No PCI

CURE: Clopidogrel 300/75 mg v Placebo (CVD/MI) 30%1 19%2

STEMI: Clopidogrel 300/75 mg v Placebo (CVD/MI) 46%3 9%4

TRITON: Prasugrel v clopidogrel 300/75mg 19%5 Not evaluated
(CVD/MI/Stroke)

1. Mehta SR, et al. Lancet 2001; 358(9281):527-33.

2. Fox KAA, et al. Circulation 2004;110:1202-8
3. Sabatine MS, et al. JAMA 2005; 294(10):1224-32.
4. Chen ZM Lancet 2005;366:1607-21
4. Boersma E et al. Lancet 2002; 359:189
5. Wiviott S et al. N Engl J Med 2007; 357: 2001–15.
 Study Design, Flow and Compliance
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
Planned Early (<24 h) Invasive Management with intended PCI
Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)

Randomized to receive (2 X 2 factorial):

CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)

Angio 24,769
(99%)
PCI 17,232 No PCI 7,855 (30%)
(70%)

No Sig. CAD 3,616 CABG 1,809 CAD 2,430

Compliance:

Clop in 1st 7d (median) 7d 7d 2d 7d

Efficacy Outcomes: CV Death, MI or stroke at day 30

Complete
Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major) Followup
Key Subgroup: PCI v No PCI 99.8%
 ASA Dose Comparison
Primary Outcome and Bleeding

ASA ASA HR 95% CI P

75-100 mg 300-325 mg
CV Death/MI/Stroke
PCI (2N=17,232) 4.2 4.1 0.98 0.84-1.13 0.76
No PCI (2N=7855) 4.7 4.4 0.92 0.75-1.14 0.44
Overall (2N=25,087) 4.4 4.2 0.96 0.85-1.08 0.47
Stent Thrombosis 2.1 1.9 0.91 0.73-1.12 0.37
TIMI Major Bleed 1.03 0.97 0.94 0.73-1.21 0.71
CURRENT Major Bleed 2.3 2.3 0.99 0.84-1.17 0.90
CURRENT Severe Bleed 1.7 1.7 1.00 0.83-1.21 1.00

GI Bleeds: 30 (0.24%) v 47 (0.38%), P=0.051

No other significant differences between ASA dose groups
Clopidogrel Dose Comparison

2 Significant Interactions:

3. PCI v No PCI (P=0.016)

5. ASA dose (P=0.043)

 Clopidogrel: Double vs Standard Dose
Primary Outcome and Components
Standard Double HR 95% CI P Intn P
CV Death/MI/Stroke
PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.036
0.016
No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14
Overall (2N=25,087) 4.4 4.2 0.95 0.84-1.07 0.370
MI
PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.012
0.025
No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23
Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097
CV Death
PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.68
1.0
No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77
Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628
Stroke
PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.59
0.50
No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67
Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950
 Clopidogrel Double vs Standard Dose
Bleeding Overall Population

Clopidogrel
Standard Double Hazard 95% CI P
N=12579 N=12508 Ratio

TIMI Major1 0.95 1.04 1.09 0.85-1.40 0.50

CURRENT Major2 2.0 2.5 1.25 1.05-1.47 0.01
CURRENT Severe3 1.5 1.9 1.23 1.02-1.49 0.03
Fatal 0.11 0.13 1.15 0.56-2.35 0.71
ICH 0.05 0.03 0.67 0.19-2.37 0.53
RBC transfusion ≥ 2U 1.76 2.21 1.26 1.06-1.51 0.01
CABG-related Major 0.9 1.0 1.10 0.85-1.42 0.48

1
ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2
Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3
Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
 Clopidogrel: Double vs Standard Dose
Definite Stent Thrombosis (Angio confirmed)

Clopidogrel Standard Dose

0.012

42%
RRR
Cumulative Hazard

0.008

Clopidogrel Double Dose

0.004

HR 0.58
95% CI 0.42-0.79
P=0.001
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 Clopidogrel: Double vs Standard Dose
Major Efficacy Outcomes in PCI Patients

Day 30 Clopidogrel
StandardN Double Hazard 95% CI P value
=8684 N=8548 Ratio
% %
Stent Thrombosis 2.3 1.6 0.71 0.57-0.89 0.002
Definite 1.2 0.7 0.58 0.42-0.79 0.001
MI 2.6 2.0 0.78 0.64-0.95 0.012
MI or stent thrombosis 3.7 3.0 0.80 0.68-0.94 0.008
CV Death 1.9 1.9 0.96 0.77-1.19 0.68
Stroke 0.4 0.4 0.88 0.55-1.41 0.59
CV Death/MI/Stroke 4.5 3.9 0.85 0.74-0.99 0.036
 Clopidogrel: Double vs Standard Dose
Primary Outcome: PCI Patients
CV Death, MI or Stroke

Clopidogrel Standard

15% RRR
0.04

Clopidogrel Double
Cumulative Hazard

0.03
0.02

HR 0.85
95% CI 0.74-0.99
0.01

P=0.036
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 Clopidogrel Double vs Standard Dose
Bleeding PCI Population

Clopidogrel
Standard Double Hazard 95% CI P
N= 8684 N=8548 Ratio

TIMI Major1 0.5 0.5 1.06 0.70-1.61 0.79

CURRENT Major2 1.1 1.6 1.44 1.11-1.86 0.006
CURRENT Severe3 0.8 1.1 1.39 1.02-1.90 0.034
Fatal 0.15 0.07 0.47 0.18-1.23 0.125
ICH 0.035 0.046 1.35 0.30-6.04 0.69
RBC transfusion ≥ 2U 0.91 1.35 1.49 1.11-1.98 0.007
CABG-related Major 0.1 0.1 1.69 0.61-4.7 0.31

1
ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal
2
Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units
3
Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units
 Clopidogrel: Double v Standard Dose
PCI Cohort Subgroups
CV Death, MI or Stroke MI or Stent Thrombosis
2N Std % Double % Intxn P Std % Double % Intxn P
Overall 17232 4.5 3.9 3.7 3.0

NSTEMI/UA 10886 4.2 3.6 3.6 3.1

STEMI 6346 5.0 4.2 0.805 4.0 2.8 0.248

Male 13009 4.1 3.6 3.5 3.0

Female 4223 5.8 4.6 0.419 4.6 3.0 0.148

Age <= 65 yrs 10975 3.0 2.7 2.9 2.2

Age > 65 yrs 6257 7.1 6.0 0.702 5.2 4.4 0.418

Non-Diabetic 13400 4.2 3.6 3.6 2.8

Prev Diabetic 3831 5.6 4.9 0.836 4.1 3.6 0.567

No Inhosp GPIIb/IIIa 12288 3.9 3.5 3.1 2.5

GPIIb in hosp 4936 6.0 4.7 0.465 5.2 4.1 0.894

No Prot Pump Inhib 7675 3.8 3.2 3.1 2.3

Prot Pump Inhib 5557 5.7 4.2 0.408 4.8 3.3 0.613

Non-smoker 10845 4.9 4.6 3.9 3.5

Current Smoker 6380 3.8 2.6 0.045 3.4 2.1 0.050

ASA Low 8620 4.2 4.3 3.6 3.2

ASA High 8612 4.8 3.5 0.024 3.8 2.7 0.191

Double Dose Std Dose Double Dose Std Dose

Better 0.50 1.50 Better Better 0.50 1.50 Better
 Clopidogrel: Double vs Standard Dose by
ASA Factorial

Clopidogrel HR 95% CI P P int’n

Standard Double
CV Death/MI/Stroke (Overall)
ASA High 4.6 3.8 0.83 0.70-0.99 0.036
ASA Low 4.2 4.5 1.07 0.91-1.27 0.42 0.043

MI/Stent Thrombosis (PCI pts)

ASA High 3.8 2.7 0.71 0.56-0.90 0.005 0.19

ASA Low 3.6 3.2 0.89 0.71-1.12 0.32
Major Bleed (Overall)
ASA High 2.2 2.4 1.08 0.86-1.37 0.51
0.099
ASA Low 1.9 2.7 1.43 1.13-1.81 0.003
 Definite Stent Thrombosis in 4 Groups
(Angiographically Proven)

C Standard, A Low
0.012

C Standard, A High
Cumulative Hazard

0.008

C Double, A Low

C Double, A High
0.004

Standard Double P
HR P
Clop Clop Intn
High ASA 1.2 0.6 0.49 0.003

Low ASA 1.2 0.8 0.6 0.058 0.35

0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 Conclusions
Clopidogrel Dose Comparison

1. Double-dose clopidogrel significantly reduced stent

thrombosis and major CV events (CV death, MI or stroke)
in PCI.

2. In patients not undergoing PCI, double dose clopidogrel

was not significantly different from standard dose (70% had
no significant CAD or stopped study drug early for CABG).

3. There was a modest excess in CURRENT-defined major

bleeds but no difference in TIMI major bleeds, ICH, fatal
bleeds or CABG-related bleeds.
 Conclusions
ASA Dose Comparison

No significant difference in efficacy or

bleeding between ASA 300-325 mg and
ASA 75-100 mg.
 Clinical Implications
• For every 1,000 patients with ACS receiving
PCI, using double-dose clopidogrel for 7 days
instead of standard dose will prevent an
additional 6 MI’s and 7 stent thromboses with
an excess of 3 severe bleeds and no increase
in fatal, CABG-related or TIMI major bleeds.
• Patients not undergoing PCI should continue to
use the standard dose regimen of clopidogrel.
 Acknowledgements
CURRENT Investigators from 597 sites in 39 countries
Steering Committee Sponsors Project Office
M. Blumenthal (Bristol-Myers Squibb) S. Chrolavicius
S. Yusuf (Chair) D. Foley P. Pais
C. Gaudin (Sanofi-Aventis) S.R. Mehta
S.R. Mehta (P.I.) M.G. Franzosi R.J.G. Peters C. Marchese (Sanofi- Aventis) A. Robinson
S. Chrolavicius C.B. Granger L. Piegas P. Hornick (Bristol-Myers Squibb) B. Jedrzejowski
A. Ajani M. Gupta J. Probstfield J. Pogue
A. Avezum S. Jolly J. Rankin R. Afzal
DSMB
J.P. Bassand C. Joyner M. Ruda L. Blake
W.E. Boden N. Karatzas Z. Rumboldt P. Sleight (Chair) W. Chen
A. Budaj A. Kastrati H.J. Rupprecht J.L. Anderson S. Di Diodato
E. Cardona J.H. Kim P.G. Steg D.L. DeMets M. Lawrence
S. Chrolavicius T.H. Koh J-F. Tanguay J. Hirsh R. Manojlovic
J. Col F. Lanas V. Valentin D.R. Holmes Jr L. Mastrangelo
P. Commerford B. Lewis J. Varigos D.E. Johnstone A. Mead
G. Di Pasquale C. Macaya H. White E. Pasadyn
R. Diaz T. Moccetti P. Widimsky Adjudication Committee T. Sovereign
J. Eha G. Montalescot D. Xavier C. Joyner (Chair) L. Wasala
J.W. Eikelboom K. Niemela J. Zhu M. Lawrence (Coordinator)
D.P. Faxon Z. Ongen J-R Zhu
M. Flather A. Orlandini Consultant: R. Peto
Supplementary Slides
 Comparison of CURRENT and TRITON

CURRENT PCI TRITON

N=17,232 N=13,608

CV Death, MI or Stroke ↓ 15% ↓ 19%

↓ 21% (w high dose ASA)
Definite Stent Thrombosis ↓ 42% ↓ 58%
↓ 51% (w high dose ASA)
TIMI Major Bleed No increase ↑ 32%
CABG-related Bleeding No increase ↑ 4-fold
Fatal bleeding No increase ↑ 4-fold
 Baseline Characteristics and In Hospital
Meds

Baseline N=25,088 Meds After Rand N=25,088

Age (y) 61.4 GP IIb/IIIa inhibitor 31.8
Female 27.4% Statin 87.2
UA/NSTEMI 70.8% Beta Blocker 82.5
Rand to Angio 3.4 h ACE/ARB 75.7
STEMI 29.2% PPI 40*
Rand to Angio 0.5 h H2 Blocker 11.3
Diabetes 23.4
Prior Stroke 4.1
Ischemic ECG Δ 80.8
↑ Biomarker 42

Variables equally balanced among the randomized groups

*38.6% low dose ASA v 41.4% high dose ASA and 40% standard dose Clop v 40% high dose Clop
22
 Clopidogrel: Double vs Standard Dose
0.05 Primary Outcome

C Std, A Hi

C Double, A Lo
0.04

C Std, A Lo
Cumulative Hazard

C Double, A Hi
0.03
0.02

Clop Clop P
HR P
Standard Double Intn
0.01

ASA 300-325 mg 4.6 3.8 0.83 0.036

0.043
ASA 75-100 mg 4.2 4.5 1.07 0.43
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 ASA Dose Comparison
Death/MI/Stroke at 30 days
0.04
0.03
Cumulative Hazard

HR 0.96 (0.85-
0.02

1.08)
P = 0.489
0.01

ASA 81-100 mg
ASA 300-325 mg
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 ASA Dose Comparison
Primary Outcome
ASA Hazard P
81-100 mg 300-325 mg Ratio 95% CI value
% %
Primary Outcome
CV Death/MI/Stroke 4.4 4.2 0.96 0.85-1.08 0.489

Components
CV Death 2.3 2.0 0.88 0.74-1.04 0.134

MI 2.1 2.0 0.97 0.82-1.15 0.726

Stroke 0.5 0.6 1.18 0.84-1.67 0.330

 ASA Dose Comparison
Death at 30 days

0.025
Cumulative Hazard

0.015

HR 0.86 (0.73-
1.02)
P = 0.077
0.005

ASA 81-100 mg
ASA 300-325 mg
0.0

0 3 6 9 12 15 18 21 24 27 30
 Secondary Outcomes (ASA)

ASA Hazard P
< 100 mg > 300 mg Ratio 95% CI value
% %

CV Death/MI/Stroke + RI 4.8 4.5 0.93 0.83-1.04 0.206

Total Death 2.5 2.2 0.86 0.73-1.02 0.077

Stent Thrombosis 1.4 1.3 0.90 0.73-1.12 0.347

Definite 0.7 0.6 0.89 0.66-1.21 0.458

Probable 0.8 0.7 0.90 0.67-1.20 0.471

 Major Bleeding at 30 Days (ASA)

ASA Hazard P
< 100 mg > 300 mg Ratio 95% CI value
% %

All Major Bleeding 2.3 2.3 0.99 0.84-1.17 0.904

Severe Bleeding 1.7 1.7 1.00 0.83-1.21 1.000

Other Major Bleeding 0.6 0.6 1.00 0.73-1.38 0.985

Minor Bleeding 4.4 4.9 1.12 1.00-1.25 0.059

 ASA Dose Comparison
Major Bleeding at 30 days

0.020
Cumulative Hazard

0.015

HR 0.99 (0.84-1.17)
0.010

P = 0.904
0.005

ASA < 100 mg

ASA > 300 mg
0.0

0 3 6 9 12 15 18 21 24 27 30

Days
 Details of Major Bleeding

ASA
81-100 300-325
mg mg
No. of Major Bleeds 287 283
Fatal 16 15
Symptomatic ICH 5 6
Surgical Intervention 49 45
Significant hypotension 56 58
(inotropes)
Hemoglobin drop > 5 g/dL 232 240
Transfusions 258 255
 Sites of Major Bleeding

ASA
81-100 mg 300-325 mg
No. of Major Bleeds 287 283
Cardiac Tamponade 27 20
Surgical 115 107
Intracranial 6 6
Retroperitoneal 11 14
Gastrointestinal 30 47*
Puncture Site 40 46

*P=0.051
 ASA Dose Comparison: Subgroups
2N 81- 100 mg 300-325 mg P interaction

Primary Composite 25087 4.4 4.2

NSTEMI 17757 4.2 3.9
STEMI 7321 4.8 5.0 0.446
Non-Diabetic 19196 4.0 3.8
Prev Diabetic 5870 5.6 5.6 0.585
GRACE <140 13394 3.0 2.8
GRACE >=140 3516 8.3 7.1 0.575
Age <= 65 yrs 15762 3.1 2.7
Age > 65 yrs 9316 6.6 6.8 0.145
No Prot Pump Inhib 15193 4.3 4.2
Prot Pump Inhib 3204 4.2 4.6 0.483
Weight >= 60kg 22504 4.1 4.1
Weight < 60kg 2358 5.7 4.7 0.339
Non-smoker 16688 4.9 4.7
Current Smoker 8369 3.3 3.1 0.977
No PCI 7855 4.7 4.4
With PCI 17232 4.2 4.1 0.724

0.4 0.7 1.0 1.3 1.6 1.9

HR (95% CI)